Although apoE is expressed abundantly in atherosclerotic lesions by the resident macrophages, the specific function of this protein in the lesion environment and its effect on atherogenesis have not been identified. To address the role of apoE specifically in lesions, a phenotype of wild-type mice in which apoE was essentially eliminated from the lesion was developed. This was done by transplanting irradiated mice with bone marrow from apoE-/- mice, which resulted in repopulation of these mice with macrophages (M) that did not express apoE in lesions. A significant reduction in diet-induced atherosclerosis was observed in these mice compared to similarly treated mice with normal M , despite similar circulating levels of lipids and apoE. This is strongly suggests that apoE in lesions is produced locally by the M , and provides compelling evidence that lesion apoE promotes atherosclerosis. Because the mechanisms responsible for the observed proatherogenic role of lesion apoE are known, this proposal addresses several possible mechanisms in the first 3 Specific Aims, and probes an alternative explanation underlying the above observation in the fourth aim. This first aim will test the hypothesis that lesion apoE promotes atherosclerosis by retaining atherogenic lipoproteins to favor foam cell formation. This will be tested by generating LDL-R/-mice with and without apoE in their lesions, and comparing the extent of atherosclerosis and lipid accumulation in the vascular walls. The second Aim will determine if apoE is necessary for facilitating cholesterol efflux out of the lesion. Contrary to popular belief that apoE facilitates HDL-mediated cholesterol efflux, the proatherogenic role of apoE suggests that it may not be essential for cholesterol efflux from lesions. This hypothesis will be tested in LDL-R-/- mice and LDL-R-/-, apoAI-/- double knockout mice by generating four phenotypes with and without lesion apoE and/or HDL. Because apoE has been shown to inhibit T cell function, the third Aim will test if lesion apoE exerts it proatherogenic effect by altering T cell functions considered to be atheroprotective. The fourth Aim will examine the possibility that the reduction in atherosclerosis of the mice transplanted with apoE-/- bone marrow was not necessarily due to the absence of apoE in the lesion, but was due to atheroprotection offered by transfer of resident bone marrow memory cells sensitized to certain antigens circulating in the hyperlipidemic apoE-/- mice. Identification of the role of apoE in lesions may lead to interventions aimed at preventing atherosclerosis.